Actuator System Comprising Lever Mechanism

ABSTRACT

The invention provides a pump assembly comprising an actuator lever, a supporting structure, a pump comprising a pump member moveable by actuation of the actuator lever, and an actuator for moving the actuator lever. A first stationary pivoting joint is formed between the actuator lever and the supporting structure, and a second floating pivoting joint is formed between the actuator lever and the pump member allowing the pump member to float relative to the actuator lever, the floating pivoting point providing a constant-length actuator arm defined between the first pivoting joint and the second pivoting joint.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/541,348 filed Sep. 29, 2006, which is a continuation of internationalapplication no. PCT/DK2005/000185 filed Mar. 18, 2005 and claimspriority of Danish application no. PA 2004 00507 filed Mar. 30, 2004 andU.S. provisional application Ser. No. 60/564,164 filed Apr. 21, 2004 allof which are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to actuators suitable for actuation ofpumps for the delivery of fluids. In a specific aspect, the inventionrelates to an actuator system suitable for actuating a membrane pumparranged in a drug delivery device adapted to be carried by a person.However, the present invention may find broad application in any fieldin which a given member, component or structure is to be moved in acontrolled manner.

BACKGROUND OF THE INVENTION

In the disclosure of the present invention reference is mostly made tothe treatment of diabetes by injection or infusion of insulin, however,this is only an exemplary use of the present invention.

Portable drug delivery devices for delivering a drug to a patient arewell known and generally comprise a reservoir adapted to contain aliquid drug and having an outlet in fluid communication with atranscutaneous access device such as a hollow infusion needle or acannula, as well as expelling means for expelling a drug out of thereservoir and through the skin of the subject via the access device.Such drug delivery devices are often termed infusion pumps.

Basically, infusion pumps can be divided into two classes. The firstclass comprises infusion pumps which are relatively expensive pumpsintended for 3-4 years use, for which reason the initial cost for such apump often is a barrier to this type of therapy. Although more complexthan traditional syringes and pens, the pump offer the advantages ofcontinuous infusion of insulin, precision in dosing and optionallyprogrammable delivery profiles and user actuated bolus infusions inconnections with meals.

Addressing the above problem, several attempts have been made to providea second class of drug infusion devices that are low in cost andconvenient to use. Some of these devices are intended to be partially orentirely disposable and may provide many of the advantages associatedwith an infusion pump without the attendant cost and inconveniencies,e.g. the pump may be prefilled thus avoiding the need for filling orrefilling a drug reservoir. Examples of this type of infusion devicesare known from U.S. Pat. Nos. 4,340,048 and 4,552,561 (based on osmoticpumps), U.S. Pat. No. 5,858,001 (based on a piston pump), U.S. Pat. No.6,280,148 (based on a membrane pump), U.S. Pat. No. 5,957,895 (based ona flow restrictor pump (also known as a bleeding hole pump)), U.S. Pat.No. 5,527,288 (based on a gas generating pump), or U.S. Pat. No.5,814,020 (based on a swellable gel) which all in the last decades havebeen proposed for use in inexpensive, primarily disposable drug infusiondevices, the cited documents being incorporated by reference.

As the membrane pump can be used as a metering pump (i.e. each actuation(or stroke) of the pump results in movement of a specific amount offluid being pumped from the pump inlet to the pump outlet side) a smallmembrane pump would be suitable for providing both a basal drug flowrate (i.e. providing a stroke at predetermined intervals) as well as adrug bolus infusion (i.e. a given number of strokes) in a drug deliverydevice of the above-described type.

More specifically, a metering membrane pump may function as follows. Inan initial condition the pump membrane is located at an initialpredefined position and the inlet and outlet valves are in their closedposition. When the means for moving the membrane (i.e. the membraneactuator) is energized an increase of the pressure inside the pumpingchamber occurs, which causes opening of the outlet valve. The fluidcontained in the pumping chamber is then expelled through the outflowchannel by the displacement of the pump membrane from its initialposition towards a fully actuated position corresponding to the endposition for the “out-stroke” or “expelling-stroke”. During this phase,the inlet valve is maintained closed by the pressure prevailing in thepumping chamber. When the pump membrane is returned to its initialposition (either due to its elastic properties or by means of themembrane actuator) the pressure in the pumping chamber decreases. Thiscauses closing of the outlet valve and opening of the inlet valve. Thefluid is then sucked into the pumping chamber through the inflowchannel, owing to the displacement of the pump membrane from theactuated position to the initial position corresponding to the endposition for the “in-stroke” or “suction-stroke”. As normally passivevalves are used, the actual design of the valve will determine thesensitivity to external conditions (e.g. back pressure) as well as theopening and closing characteristics thereof, typically resulting in acompromise between the desire to have a low opening pressure and aminimum of backflow. As also appears, a metering membrane functions asany conventional type of membrane pump, for example described for use asa fuel pump in U.S. Pat. No. 2,980,032.

As follows from the above, the precision of a metering pump is to alarge degree determined by the pump membranes movement between itsinitial and actuated positions. These positions may be determined by thepump cavity in which the pump membrane is arranged, i.e. the membrane ismoved between contact with two opposed surfaces, this allowing e.g. thepump to be driven by an expanding gas (see PCT/DK03/00628), or they maybe determined by a membrane actuator member being moved betweenpredefined positions. Indeed, to secure a high delivery precision itwould be desirable to monitor that the pump membrane is actually movedbetween its two positions. Membrane movement may be measured using anyconvenient means such as electrical contacts or electrical impedancemeasurement (resistance or capacitance) between electricalcontacts/elements arranged on opposed surfaces of the pump membrane andthe pump housing.

Instead of, or in addition to, monitoring the pump per se it is alsopossible to positively detect the flow rate from any given type of pumpby incorporating additional metering means, e.g. based onthermo-dilution as disclosed in EP 1 177 802.

To further monitor proper functioning of an actuated system such as adrug infusion pump, it would be desirable to provide means for detectingdifferent operational conditions of the system, such as an occlusioncondition downstream of a pump, e.g. full or partial occlusion of atranscutaneous access device. As the outlet conduit leading from thepump outlet to the distal outlet opening of a transcutaneous accessdevice is relatively stiff, a given pressure rise in the outlet conduitduring pump actuation can normally be taken as an indication for anocclusion condition and thus be utilized to detect the latter. Forexample, US 2003/167035 discloses a delivery device comprising pressuresensors being actuated by a resilient diaphragm arranged in flowcommunication with in the outlet conduit.

Having regard to the above-identified problems, it is an object of thepresent invention to provide an actuator system, or component thereof,suitable for driving an actuatable structure or component.

It is a further object to provide an actuator system which allows fordetection of different operational conditions of the system, therebyideally providing a system which can be actuated and controlled in asafe and efficient manner.

It is a further object to provide an actuator system which can be usedin combination with a pump assembly arranged in a portable drug deliverydevice, system or a component therefore, thereby providing controlledinfusion of a drug to a subject.

It is a further object to provide an actuator system which can be usedin combination with a pump such as a membrane pump.

It is a further object of the invention to provide an actuator, orcomponent thereof, which can be provided and applied in a cost-effectivemanner.

DISCLOSURE OF THE INVENTION

In the disclosure of the present invention, embodiments and aspects willbe described which will address one or more of the above objects orwhich will address objects apparent from the below disclosure as well asfrom the description of exemplary embodiments.

According to a first aspect of the invention, an actuator system isprovided comprising an actuator lever, a supporting structure, amoveable structure moveable by actuation of the actuator lever, and anactuator for moving the actuator lever. A first stationary pivotingjoint (in the following the term pivot joint may be used as anequivalent term) is formed between the actuator lever and the supportingstructure, and a second floating pivoting joint is formed between theactuator lever and the moveable structure allowing the moveablestructure to float relative to the actuator lever, the floating pivotingpoint providing a constant-length actuator arm defined between the firstpivoting joint and the second pivoting joint. By this arrangement thelever is attached to the supporting structure, however, as the jointbetween the lever and the moveable structure is floating, the moveablestructure is allowed (to a certain degree) to move relative to thesupporting structure (and visa versa) yet still preserving the armlength and thus the ability to actuate a structure in a controlled andefficient manner.

In an embodiment thereof an actuator system is provided comprising anactuator lever, a supporting structure, a moveable structure beingmoveable by actuation of the actuator lever, and an actuator providingan actuation force at an actuator position on the actuator lever. Afirst stationary pivoting joint is formed between the actuator lever andthe supporting structure, whereby a first actuator arm length is definedbetween the first pivoting joint and the actuator position. A secondfloating pivoting joint is formed between the actuator lever and themoveable structure allowing the moveable structure to float relative tothe actuator lever, whereby the floating pivoting point provides asecond constant-length actuator arm being defined between the firstpivoting joint and the second pivoting joint.

In an alternative configuration an actuator system is providedcomprising an actuator lever, a supporting structure, a moveablestructure moveable by actuation of the actuator lever, and an actuatorfor moving the actuator lever. A first floating pivoting joint is formedbetween the actuator lever and the supporting structure allowing theactuator lever to float relative to the supporting structure, and asecond floating pivoting joint is formed between the actuator lever andthe moveable structure allowing the actuator lever to float relative tothe moveable structure, the floating pivoting points providing aconstant-length actuator arm being defined between the first pivotingjoint and the second pivoting joint. By this arrangement the lever isallowed (to a certain degree) to move relative to the supportingstructure as well as the actuated structure yet still preserving the armlengths.

In an embodiment thereof an actuator system is provided comprising anactuator lever, a supporting structure, a moveable structure beingmoveable by actuation of the actuator lever, and an actuator providingan actuation force at a predefined actuator position on the actuatorlever. A first floating pivoting joint is formed between the actuatorlever and the supporting structure allowing the actuator lever to floatrelative to the supporting structure, whereby a first constant-lengthactuator arm is defined between the first pivoting joint and theactuator position. A second floating pivoting joint is formed betweenthe actuator lever and the moveable structure allowing the actuatorlever to float relative to the moveable structure, whereby the floatingpivoting point provides a second constant-length actuator arm definedbetween the first pivoting joint and the second pivoting joint.

For both alternatives the second joint may be arranged between the firstjoint and the actuator position, or the first joint may be arrangedbetween the second joint and the actuator position.

The floating joints are advantageously formed by a line bearing (e.g.formed by a knife-edge or rounded rod member) or point bearing (e.g.formed from a pointed member or a ball) formed on the actuator levercooperating with a substantially planar surface allowing the knife-edgeor ball bearing to float relative thereto. In the present context such aplanar surface would also include a groove in which a point formedmember would be allowed to float. By this arrangement the actualposition of a floating joint will be determined by the position of theknife-edge or ball bearing and thus by the lever, the planar surface ofthe other structure being allowed to move without changing the length ofthe lever arms.

To hold the contact structures of the joints (especially the floatingjoints) in contact with each other, a biasing member may be provided. Asan example, the actuator may be of the coil-magnet type, the coil andmagnet(s) being arranged on the actuator lever respectively thesupporting structure. As long as the magnetic relationship issubstantially constant (e.g. the coil is positioned within a (near)constant magnet field, the force provided by the moving component (i.e.arranged on the lever) will substantially constant.

In an exemplary embodiment the actuator system is provided incombination with a pump for pumping a liquid between an inlet and anoutlet thereof, the pump comprising a pump member performing a pumpstroke when actuated by the actuator lever. The pump may comprise inletand outlet valves associated with the pump inlet respectively the pumpoutlet, and a pump chamber in which the pump member is moved to performa pump stroke respectively a suction stroke. The combination may furthercomprise a reservoir adapted to contain a fluid drug and comprising anoutlet in fluid communication with or being adapted to be arranged influid communication with the pump inlet, and a transcutaneous accessdevice comprising a distal end adapted to be inserted through the skinof a subject, the transcutaneous access device comprising an inlet influid communication with or being adapted to be arranged in fluidcommunication with the pump outlet, the combination thereby providing adrug delivery device. The reservoir may be any suitable structureadapted to hold an amount of a fluid drug, e.g. a hard reservoir, aflexible reservoir, a distensible or elastic reservoir. The reservoirmay e.g. be prefilled, user fillable or in the form of a replaceablecartridge which again may be prefilled or fillable.

When actuating a given member, it would be desirable to provide anactuator system which allows for detection of different operationalconditions of the system, thereby ideally providing a system which canbe actuated and controlled in a safe and efficient manner.

Correspondingly, according to a further aspect of the invention, anactuator system is provided comprising an actuator member for moving astructure, the actuator member having a first position and a secondposition, and actuating means for moving the actuator member between thefirst and second positions. The system further comprises detection meansfor detecting the first respectively the second position and supplyingsignals indicative thereof (e.g. when a position was reached or left),and a controller for determining on the basis of the supplied signalsthe time lapsed when the actuator member is moved between the first andsecond positions in a given direction, e.g. T-in or T-out for a suctionrespectively an expelling pump stroke. The controller is provided withinformation representing at least one defined time range, each timerange being associated with movement of the actuator member in a givendirection between the first and second positions and a given actuationforce, e.g. as determined by a supplied current, the controller beingadapted to compare the determined time lapsed with the one or moredefined time ranges and perform an action corresponding to the timerange associated with the determined time lapsed.

The time range(s) may be predefined, selectable or they may bedynamically influenced by actuation history over a short or long periodof time. The time range(s) may be closed, open or open-ended. The actionmay be in the form of a “positive” action, e.g. actuating an alarm,initiating a modified actuation pattern, or a “negative” action, e.g. noaction. The motion provided by the actuator may be e.g. reciprocating,linear or rotational, which movement may then be trans-formed into thedesired actuation pattern for a given structure to be moved.Correspondingly, the actuator means may be of any suitable type, e.g. acoil-magnet system, a shape memory alloy (SMA) actuator, a solenoid, amotor, a gas generator, a piezo actuator, a thermo-pneumatic actuator,or a pneumatic actuator.

In the context of the present application and as used in thespecification and claims, the term controller covers any combination ofelectronic circuitry suitable for providing the specified functionality,e.g. processing data and controlling memory as well as all connectedinput and output devices. The controller may comprise one or moreprocessors or CPUs which may be supplemented by additional devices forsupport or control functions. For example, the detection means, atransmitter, or a receiver may be fully or partly integrated with thecontroller, or may be provided by individual units. Each of thecomponents making up the controller circuitry may be special purpose orgeneral purpose devices. The detection means may comprise a “sensor” perse, e.g. in the form of an electrical contact, or an optical or magneticsensor capable of being influenced by the position of the actuatormember, in combination with circuitry supplying time signals indicativeof when a position was reached or left. Such circuitry may be formedfully or partly integrally with the controller. For example, both mayrely on a common clock circuit. As appears, the distinction between thedetection means and the controller may be more functional rather thanstructural.

As appears, for each direction and each force a number of defined timeranges may be provided, however, in the simplest form only a single timerange associated with movement of the actuator in one direction isprovided. For example, a determined time lapsed within such a singletime range may indicate an alarm or malfunctioning condition whereaslapsed times outside this range would be considered within normaloperation. In a more advanced form a number of time ranges is providedfor each direction. The time ranges may be “closed” (e.g. 50-100 ms) or“open” (e.g. >50 ms or <100 ms).

As appears, it is important that a determined lapsed time is correctlycorrelated with a given actuator movement. Thus, in an exemplaryembodiment the controller is adapted to control the actuating means formoving the actuator between the first and second positions in a givendirection, and determine a lapsed time corresponding to a givenactuation of the actuator member between the first and second positionsin a given direction. However, a given actuator movement may also be“passive”, i.e. provided by forces not “actively” generated by actuatormeans. For example, an actuated movement may be followed immediately bya passive movement (e.g. provided by an elastic member deformed duringthe active movement, the elastic member then serving as an actuator)which could then be correlated to the former.

To further control the relation between movement and time, thecontroller may be adapted to determine on the basis of signals suppliedby the detection means that the actuator is correctly positioned ineither the first or the second position corresponding to the givendirection of actuation, and provide a signal (e.g. error or alarmsignal) in case the actuator member is not correctly positionedcorresponding to the given direction of actuation.

To provide time signals well correlated to the first and secondpositions, an exemplary embodiment of the system comprises first andsecond stop means adapted to engage the actuator member in the firstrespectively the second position, whereby engagement between theactuator member and the first respectively the second stop means allowsthe detection means to detect that the actuator member is in the firstrespectively the second position. It should be emphasized that the term“actuator member” in this context may be a structure of the actuatormember per se (e.g. an actuator lever) or a component functionally andmotionally coupled to the actuator member (e.g. a component moved by theactuator such as a piston or a pump membrane) such that the first andsecond positions for such a component correspond to the first and secondpositions for the actuator member per se. Detection of the “stop”positions may be by any suitable detection means, e.g. comprisingelectrical contacts, optical or magnetic sensors.

As stated above, the time range(s) may be predefined, selectable or theymay be dynamically determined. For example, upon initial use of a givenactuated system, the system may be actuated a number of times (e.g. whenpriming a pump), and the lapsed times detected during these actuationsbe used to determine a value which is unique for the actual system,which value may then be used to calculate one or more defined ranges tobe used for the subsequent determination of different conditions for thesystem. As a safety feature, the actuator system may be provided withpreset values or ranges within which the dynamically determined rangesshould fall, this to prevent that a dynamic range is determined for adefective system.

As stated in the introductory portion, the actuator system of thepresent invention may find broad application in any field in which agiven member, component or structure is to be moved in a controlledmanner. In an exemplary embodiment the actuator system is provided incombination with a pump for pumping a liquid between an inlet and anoutlet thereof, the pump comprising a pump member performing a pumpaction when actuated by the actuator member moved between the first andsecond positions. The pump may be of any desired type, e.g. a membranepump, a piston-cylinder pump or a roller-tube pump. The actuator systemof the present invention may be used to monitor and detect normaloperations of the system as well as operations associated with amalfunctioning of the system or the application in which a given pump isused.

For example, the pump outlet of a drug delivery device may be in fluidcommunication with a hydraulically rigid outlet conduit, such that apartial or full occlusion of the outlet conduit (e.g. corresponding to adistal outlet opening of conduit such as a distal opening of a cannulaor a hollow needle) will result in a substantially unrestricted pressurerise in the outlet conduit, whereby for a predetermined actuation forceapplied to the pump member from the actuation member the duration of thepump stroke will be extended. To detect such a condition the controlleris provided with information representing a defined time rangeindicative of an occlusion condition in the outlet conduit, thecontroller being adapted to produce an alarm signal in case thedetermined lapsed time of a pump stroke is within the occlusioncondition time range. The alarm signal may be used to activate anassociated user alarm such as an audible, visual or tactile alarm, or itmay be used to initially try to overcome the occlusion by modifying pumpoperation.

The pump may comprise inlet and outlet valves associated with the pumpinlet respectively the pump outlet, and a pump chamber in which the pumpmember is moved to perform a pump stroke respectively a suction stroke,the suction stroke being associated with the actuator member being movedbetween the second and first positions. For such a combination thecontroller may comprise information representing one or more of thefollowing defined time ranges for a given actuation force and/ordirection: (a) a time range associated with normal pump operation duringa pump stroke, (b) a time range associated with a shortened pump stroke,(c) a time range associated with a prolonged pump stroke, (d) a timerange associated with normal pump operation during a suction stroke, (e)a time range associated with a shortened suction stroke, and (f) a timerange associated with a prolonged suction stroke, where the controllerbeing adapted to compare the determined time lapsed with the definedtime range(s) and perform an action corresponding to the time rangeassociated with the determined time lapsed. Depending on the state ofthe pump a given time range may define different conditions, e.g. duringpriming of the pump and during normal operation of the pump, a givenrange may correlate to different situations. Further time ranges may bedefined based upon the above time ranges, e.g. for each time range alower and an upper time range may be defined, or the different timeranges may be used to calculate combined time ranges, e.g. a sum ordifference of two ranges or an average of two ranges.

Such a combination may further comprise a reservoir adapted to contain afluid drug, the reservoir comprising an outlet in fluid communicationwith, or being adapted to be arranged in fluid communication with, thepump inlet. The combination may further comprise a transcutaneous accessdevice comprising a pointed end adapted to penetrate the skin of asubject, the access device comprising an inlet in fluid communicationwith, or being adapted to be arranged in fluid communication with, thepump outlet. For such a device the different time ranges (a)-(f) may beused to detect different conditions during operation of the pump. Forexample, (a) may be used to indicate normal pump operation, (b) toindicate that air is pumped instead of liquid, e.g. during priming ofthe pump or when the pump is sucking air due to a leak, or that theinlet valve is malfunctioning (c) to indicate a further occlusionsituation, e.g. more severe, (d) to indicate normal pump chamber fillingduring operation, (e) to indicate inlet valve malfunctioning, and (f) toindicate that a non-vented reservoir is close to empty. As indicated,the time ranges are associated with a given actuation force, such thatit may be necessary to have two or more sets of ranges if it isdesirable to operate the actuation means at different levels. Forexample, a coil-magnet actuator may be operated at different currentlevels, e.g. 1V, 2V and 3V dependent upon the operational requirements.The actuator may start operate e.g. a pump at 1V and if an occlusionsituation is detected, the current may be raised to overcome theobstruction. Indeed, for such a higher current a different set of timeranges will be relevant.

The present invention also provides a method for operating a pump havinga moveable pump member, comprising the steps of (i) actuating the pumpmember between first and second positions, (ii) determining the timelapsed when the pump member is moved between the first and secondpositions in a given direction and under given conditions, (iii)comparing the determined time lapsed with one or more defined timeranges, and (iv) performing an action corresponding to the time rangeassociated with the determined time lapsed. One or more time ranges mayeither be predetermined or calculated on basis of previously determinedtimes lapsed. The pump may comprise an inlet in fluid communication witha liquid filled reservoir, and an outlet in fluid communication with atranscutaneous access device, wherein the defined time range(s) is/areassociated with one or more of the following conditions, an empty ornear-empty reservoir, pumping of air, pumping of liquid, obstruction ofthe inlet, obstruction of the outlet, obstruction of the transcutaneousaccess device, and pump malfunctioning.

The invention also provides a method of controlling an actuator member,comprising the steps of (i) providing an actuator member suitable formoving a structure, the actuator member having a first position and asecond position, (ii) providing an actuator for moving the actuatormember between the first and second positions, (iii) providing adetector for detecting the first respectively the second position andsupplying time signals indicative thereof, (iv) providing a controllercomprising information representing at least one defined time range,each time range being associated with movement of the actuator member ina given direction between the first and second positions and a givenactuation force, (v) actuating the actuator to thereby move theactuation member, (vi) supplying time signals to the controller, (vii)determining on the basis of supplied time signals the time lapsed whenthe actuator member is moved between the first and second positions in agiven direction, (viii) comparing the determined time lapsed with one ormore defined time ranges, and (ix) performing a control actioncorresponding to the time range associated with the determined timelapsed.

For many mechanical systems static frictional forces will be relevant.If this is the case in a given system operated by the above-describedactuator system, it may be desirable to “ramp up” the actuation force tothereby prevent “overshoot” and thereby too fast movement between thetwo positions which would render it more difficult to discriminatebetween different conditions.

A further strategy to detect an occlusion situation for a pump is basedon the principle of detecting the force (or a value representativethereof) necessary to move the pump actuator away from the first (i.e.initial) position. By slowly ramping up the force (e.g. current througha coil) it will be possible to detect the force necessary to overcome astatic friction force as well as the pressure in the system. In this waythe current may be utilized to detect an occlusion situation. Further,when an initially empty pump is primed, air is pumped having a very lowviscosity which can be used to detect properties of the pump system,e.g. static friction and elastic properties of a pump membrane. Forexample, when the pump is primed the energy necessary for driving thepump membrane between its initial and actuated positions can bedetermined. When subsequently the energy necessary for driving the pumpmembrane between its initial and actuated positions when liquid ispumped is determined, the difference between the energies can be used tocalculate the energy used for the pump work and thus the pressure in thepump system. When liquid is pumped under normal operation conditions,pump actuation may be controlled to achieve pump time cycles under whichthe pump operates most efficiently, e.g. to ensure that the valvesoperate efficiently with minimum back-flow.

As used herein, the term “drug” is meant to encompass anydrug-containing flowable medicine capable of being passed through adelivery means such as a hollow needle in a controlled manner, such as aliquid, solution, gel or fine suspension. Representative drugs includepharmaceuticals (including peptides, proteins, and hormones),biologically derived or active agents, hormonal and gene based agents,nutritional formulas and other substances in both solid (dispensed) andliquid form. In the description of the exemplary embodiments referencewill be made to the use of insulin. Correspondingly, the term“subcutaneous” infusion is meant to encompass any method of parenteraldelivery to a subject.

BRIEF DESCRIPTION OF THE DRAWINGS

In the following the invention will be further described with referencesto the drawings, wherein

FIG. 1 shows an exploded view of an embodiment of an actuator incombination with a pump,

FIGS. 2A-2C show schematic cross-sectional views through a pump andactuator assembly in different stages of actuation,

FIGS. 3A and 3B show schematic cross-sectional views through a part of afurther pump and actuator assembly,

FIG. 4 shows a cross-sectional view through piston rod mounted in apump,

FIG. 5 shows an exploded view of a further embodiment of an actuator,

FIG. 6 shows the actuator of FIG. 5 in an assembled state,

FIG. 7 shows a cross-sectional view of the actuator of FIG. 5,

FIG. 8 shows the actuator of FIG. 5 in an assembled state with a flexprint mounted,

FIGS. 9A-9C show cross-sectional views through the actuator assembly ofFIG. 5 in different stages of actuation,

FIG. 10 shows in an exploded perspective view a drug delivery devicecomprising a pump and actuator assembly,

FIG. 11 shows a perspective view of the interior of a pump unit,

FIG. 12 shows a schematic overview of a pump connected to a reservoir,

FIG. 13 shows an exploded view of a pump assembly,

FIG. 14 shows a cross-sectional view of the pump assembly of FIG. 13,

FIGS. 15 and 16 show partial cross-sectional views of the pump assemblyof FIG. 13,

FIG. 17 shows a diagram representing controller evaluation of actuatorderived information,

FIGS. 18-22 show T-in and T-out values in milliseconds (ms) fordifferent pump conditions during actuation of a pump, and

FIG. 23 shows in principle a voltage/time relationship during pumpactuation.

In the figures like reference numerals are used to mainly denote like orsimilar structures.

DESCRIPTION OF EXEMPLARY EMBODIMENTS

When in the following terms as “upper” and “lower”, “right” and “left”,“horizontal” and “vertical” or similar relative expressions are used,these only refer to the appended figures and not to an actual situationof use. The shown figures are schematic representations for which reasonthe configuration of the different structures as well as their relativedimensions are intended to serve illustrative purposes only.

More specifically, a pump actuator 1 comprises an upper housing member10 and a lower housing member 20, both comprising a distal main portion11, 21 and a therefrom extending proximal arm portion 12, 22. On anupper surface of the lower main portion a pair of opposed walls 23, 24are arranged and at the proximal end of the lower arm a post member 25and a knife-edge member 26 are arranged perpendicularly to the generalplane of the lower arm. In an assembled state the two main portions forma housing in which a pair of magnets 40, 41 is arranged on the opposedupper and lower inner surfaces of the main portions. The pump actuatorfurther comprises a lever 30 having a proximal end 31 comprising firstand second longitudinally offset and opposed joint structures in theform of a groove 33 and a knife-edge 34 arranged perpendicular to alongitudinal axis of the lever, and a distal end 32 with a pair ofgripping arms 35 for holding a coil member 36 wound from a conductor. Amembrane pump is arranged in a pump housing 50 having a bore in which anactuation/piston rod 51 is arranged, the rod serving to actuate the pumpmembrane of the membrane pump (see below for a more detailed descriptionof the membrane pump). The outer free end of the rod is configured as asubstantially planar surface 52. In an assembled state the lever isarranged inside the housing with the coil positioned between the twomagnets, and the housing is attached to the pump housing with theknife-edge of the knife-edge member 26 nested in the lever groove 33 andthe knife-edge of the lever is positioned on the planar rod end surface,this arrangement providing first and second pivoting joints. As theactuating rod is biased outwardly by the elastic pump membrane the leveris held in place by the two joints and the housing in combination, thelever only being allowed to pivot relative to the first joint (see alsobelow). Due to this arrangement a gearing of the force provided from thecoil-magnet actuator to the actuation rod is realized, the gearing beingdetermined by the distance between the two pivoting joints (i.e. a firstactuator arm) and the distance between the first/proximal pivoting jointand the “effective” position of the coil on the lever (i.e. a secondactuator arm). By the term “effective”, the issue is addressed that theforce generated by the coil actuator may vary as a function of therotational position of the lever, this being due to the fact that thecoil is moved between stationary magnets, which may result in a varyingmagnetic field for the coil as it is moved. The actuator furthercomprises a pair of contact members 28, 29 adapted to cooperate with acontact rod 37 mounted in the housing and which will be described withreference to FIG. 3A.

FIGS. 2A-2C show schematic cross-sectional views through a pump andactuator assembly of the type shown in FIG. 1, the sectionscorresponding to a plane above the lever. Corresponding to the FIG. 1embodiment, the assembly comprises a housing 120 for accommodating theactuator lever 130, a pair of magnets 140 as well as a pump assembly150, the housing comprising a knife-edge member 126. The pump assemblymay be of the type disclosed in FIGS. 11-16. The actuator levercomprises first and second grooves 133, 134, a coil 136 and a contactrod 137 adapted to engage first and second contact members 128, 129arranged on the housing. The lever further comprises a pair ofconductors 138 for energizing the coil as well as a conductor 139 forthe contact rod. In the shown embodiment the conductors are shown withterminal contact points, however, advantageously the three conductorsare formed on a flex-print attached to the lever and connected to astructure of the device in which the actuator is mounted, the connectionbetween the moving lever and the other structure being provided by afilm hinge formed by the flex-print. The pump comprises a pump chamber153, in which an elastic pump membrane 154 is arranged, and a bore 156for slidingly receive and support a piston rod 151 with a convex pistonhead 155 engaging the pump membrane. The pump membrane is in allpositions in a stretched state, the membrane thereby exerting a biasingforce on the piston rod which is used to hold the actuator lever inplace as described above. The pump further comprises an inlet conduit160 with an inlet valve 161 in fluid communication with the pumpchamber, and an outlet conduit 170 with an outlet valve 171 in fluidcommunication with the pump chamber. The valves may be of any desirableconfiguration, but advantageously they are passive membrane valves.

FIG. 2A shows the pump and actuator assembly in an initial state withthe actuator lever in an initial position in which the contact rod 137is positioned against the first contact member 128 which thereby servesas a stop for the lever. As indicated above, the piston rod 151 has alength which ensures that it is forced by the pump membrane into contactwith the lever in its initial position. The terms “initial” and“actuated” state refers to the shown embodiment in which the actuator isused to actuate the pump to produce a pump stroke, however, although thesuction stroke of the pump may be passive (i.e. performed by the elasticenergy stored in the pump membrane during the pump stroke) the actuatormay also be actuated in the reverse direction (i.e. from the actuated tothe initial position) to actively drive the pump during the suctionstroke. Thus, in more general terms the actuator is moved between firstand second positions in either direction.

FIG. 2B shows the pump and actuator assembly in an intermediate state inwhich the coil 136 has been energized (e.g. by a ramped PWM pulse)pivoting the lever relative to the first pivot joint 126, 133 therebyactuating the pump membrane via the piston 151, 155. As appears, thecontact rod is now positioned between the two contact members 128, 129.

FIG. 2C shows the pump and actuator assembly in a fully activated statewith the actuator lever in a fully actuated position in which thecontact rod 137 is positioned against the second contact member 129which thereby also serves as a stop for the lever. In this way thestroke distance and thus the stroke volume of the pump membrane isdetermined by the two contact (or stop) members 128, 129. In thisposition the coil is de-energized and the actuator lever is returned toits initial position by means of the biasing force of the pump membranewhich during its travel to its initial position performs a suctionstroke. If desirable, the actuator lever may also be returned to itsinitial position actively by reversing the current flow in the coil,however, in order to keep the actuator rod and the lever in contact witheach other, this actuation should not be too swift.

FIG. 3A shows an alternative embodiment in which the actuator levercomprises two knife-edge members 233, 234 which cooperate withsubstantially planar surfaces on the housing support 226 and the freepiston end 252 to provide first and second pivoting joints. By thisarrangement the distance between the two pivoting points, and thus thepiston stroke length, is determined by properties of the lever which isallowed to “float” with respect to the two planar joint surfaces.Indeed, the housing should be provided with appropriate stops (notshown) preventing the lever from dislocating out of engagement. Further,two contact members 228, 229 are arranged on the lever cooperating witha contact rod 237 mounted on the housing, the opposed surfaces of therod thereby serving as first and second stop means adapted to engage theactuator member in the initial respectively the actuated position. Inthis way the rotational freedom of the lever relative to the firstpivoting joint, and thus the piston stroke length, is determined by theposition of the contact members and the diameter of the contact rod. Asappears, by this arrangement the structures most important forcontrolling the stroke length of the piston are all provided as parts ofthe lever. In an alternative embodiment (corresponding to FIG. 1) thehousing support 226 comprises a groove in which the first knife-edgemember 233 is located. In this way the lever is no longer allowed to“float”, however, due to the planer surface 252 on the piston, thestroke length is controlled by the position of the knife-edge membersand not the precise position of the piston relative to the housingsupport groove. A non-floating joint between the housing and the leveris not limited to a knife-edge joint but may have any desirableconfiguration, e.g. a film hinge joint. Further, the line-contact jointprovided by a knife-edge joint may be replaced by a punctual-contactjoint provided by e.g. a spherical member resting on a planar surface.In the shown embodiment two pair of conductors 238, 239 are supplied tothe coil respectively the contact members, however, alternatively thecontact members may be connected to the coil conductors which then mayserve to both energize the coil and conduct contact information to aprocessor or control system (not shown). For example, in case thecontact rod is provided with a given resting voltage this voltage willchange as the coil is energized with the contact rod in contact with thefirst contact member 229 and will change again as the second contactmember 228 is moved into contact with the contact rod.

In the FIGS. 2 and 3 embodiments the piston-lever joint is providedbetween the housing-lever joint and the actuator coil, however, thepositions may also be reversed such that the housing-lever joint isarranged between the piston-lever joint and the coil (not shown).

In FIGS. 2 and 3 the rotational (pivoting) freedom for the actuatorlever has been provided by structures associated with the lever,however, in an alternative embodiment shown in FIG. 4 the structurescontrolling rotational lever movement and providing contact informationare associated with the piston rod. More specifically, the piston rod356 comprises first and second collar members 358, 357 forming a gap inwhich a stop member 380 connected to the pump housing is arranged. Inthis way piston stroke length is determined by the thickness of the stopmember and the distance between the two collar members. In the shownembodiment the two collar members are formed from metal and cooperatewith a pair of conductors 381 arranged on the stop member.

With reference to FIG. 5 a further pump actuator will be described.Although the figure is oriented differently, the same terminology as forFIG. 1 will be used, the two pump actuators generally having the sameconfiguration. The pump actuator 500 comprises an upper housing member510 and a lower housing member 520, both comprising a distal mainportion 511, 521 and a there from extending proximal arm portion 512,522. Extending from the lower main portion a pair of opposed connectionmembers 523, 524 are arranged, and at the proximal end of the lower arma proximal connection member 525 is arranged perpendicularly to thegeneral plane of the lower arm, the proximal connection member servingas a mount for a joint mount 527 comprising a slot for receiving an axlerod. Further, a separate proximal connection member 526 is provided. Inan assembled state the two main portions and the proximal connectionmember form a housing in which two pair of magnets 540, 541 are arrangedon the opposed upper and lower inner surfaces of the main portions. Thepump actuator further comprises a lever 530 having a proximal end 531comprising first and second longitudinally offset and opposed jointstructures in the form of an axle rod 533 respectively a joint rod 534arranged perpendicular to a longitudinal axis of the lever, and a distalend 532 with a pair of gripping arms 535 for holding a coil member 536wound from a conductor. A membrane pump (not shown) comprises anactuation/piston rod 551 is arranged, the piston rod serving to actuatethe pump membrane of the membrane pump. The outer free end of the rod isconfigured as a substantially planar surface 552. The actuator furthercomprises a pair of rod-formed contact members 528, 529 mounted on thedistal end of the lever and adapted to cooperate with a contact rod 537mounted in the proximal connection member. Although the two joint rods533, 534 and the contact members 528, 529 are shown as separate members,they are preferably all metallic members moulded into a lever formedfrom a polymeric material.

In an assembled state as shown in FIG. 6 (the lower housing member notbeing shown for clarity reasons) the lever is arranged inside a housingformed by the upper and lower housing members and the proximalconnection member, with the coil positioned between the two pair ofmagnets. The axle rod 533 is arranged in the slot of the joint mountthereby forming a proximal pivot joint. When the actuator is attached toa pump assembly (see e.g. FIG. 11) the joint rod 534 engages thesubstantially planar end surface 552 of the piston rod, thereby forminga distal floating knife-edge pivot joint. Although the joint rod is nota “knife”, the circular cross-sectional configuration of the rodprovides a line of contact between the rod and the end surface, and thusa “knife-edge” joint. Using a more generic term, such a joint may alsobe termed a “line” joint. Due to this arrangement a gearing of the forceprovided from the coil-magnet actuator to the actuation rod is realized,the gearing being determined by the distance between the two pivotjoints and the distance between the proximal pivot joint and the“effective” position of the coil on the lever. As the piston rod isbiased outwardly by the elastic pump membrane the lever is held in placeby the two joints and the housing in combination, the lever only beingallowed to pivot relative to the first joint (see also below).

In the cross-sectional view of FIG. 7 it can be seen how the axle rod533 is arranged in the slotted joint mount 527 (e.g. by snap-action) toform a pivot joint (which in the shown configuration may also be termeda bearing), and how the joint rod 534 engages the free end of the pistonrod 551 to form a floating knife-edge pivot joint. Further, the contactmembers 528, 529 embedded in the lever 530 can be seen.

In order to provide electrical connections between the electricalcomponents of the actuator, i.e. the contact members and the coil, andcontroller circuitry (see FIG. 11) the assembled actuator is providedwith a flex print as seen in FIG. 8. The flex print comprises a mainportion 560 mounted to the housing of the actuator, a lever portion 561mounted to the lever, and a connecting portion 562 providing connectionwith the controller electronics. A film hinge 563 is provided betweenthe main portion and the lever portion, this allowing the lever to pivotsubstantially freely. The flex print may be attached by any suitablemeans, e.g. adhesives or mechanical connectors.

FIGS. 9A-9C show cross-sectional views through an actuator assembly ofthe type shown in FIG. 5, the sections corresponding to a plane throughthe lever. The actuator is shown in an engagement with a piston rod 551of a membrane pump (not shown) of the same principle configuration asshown in FIG. 2A. The pump membrane is in all positions in a stretchedstate, the membrane thereby exerting a biasing force on the piston rodwhich is used to hold the actuator lever in place as described above.

FIG. 9A shows the piston rod and actuator assembly in an initial statewith the actuator lever in an initial position in which the contact rod537 is positioned against the first contact member 528 which therebyserves as a stop for the lever. A proximal non-floating pivot joint isformed between the axle rod 533 and the slotted joint mount 527, and adistal floating pivot joint is formed between the joint rod 534 and theupper end of the piston rod 551. By this arrangement the distancebetween the two pivot points, and thus the piston stroke length, isdetermined by properties of the lever, whereas the lever and the pistonrod is allowed to “float” with respect to each other. Further, the twocontact members 528, 529 arranged on the lever cooperate with thecontact rod 537 mounted on the housing, the opposed surfaces of the rodthereby serving as first and second stop means adapted to engage theactuator member (here: the lever) in the initial respectively theactuated position. In this way the rotational freedom of the leverrelative to the first pivot joint, and thus the piston stroke length, isdetermined by the position of the contact members and the diameter ofthe contact rod. As appears, by this arrangement the structures mostimportant for controlling the stroke length of the piston are allprovided as parts of the lever. As indicated above, the piston rod 551has a length which ensures that it is forced by the pump membrane intocontact with the lever in its initial position. As for the embodiment ofFIGS. 3A-3C the terms “initial” and “actuated” refers to the shownembodiment in which the actuator is used to actuate the pump to producea pump stroke.

FIG. 9B shows the actuator assembly in an intermediate state in whichthe coil 536 has been energized pivoting the lever relative to theproximal pivot joint 533, 527 thereby actuating the pump membrane viathe piston 551. As appears, the contact rod is now positioned betweenthe two contact members 528, 529.

FIG. 9C shows the actuator assembly in a fully activated state with theactuator lever in a fully actuated position in which the contact rod 537is positioned against the second contact member 529 which thereby alsoserves as a stop for the lever. In this way the stroke distance and thusthe stroke volume of the pump membrane is determined by the two contact(or stop) members 528, 529. In this position the coil is de-energizedand the actuator lever is returned to its initial position by means ofthe biasing force of the pump membrane which during its travel to itsinitial position performs a suction stroke. If desirable, the actuatorlever may also be returned to its initial position actively by reversingthe current flow in the coil.

As appears from the above, the two contact/stop members serve to controlthe stroke volume of the pump, however, they may also be used to controloperation and performance of the actuated component (e.g. a pump) andthe system/device in which it is embedded. More specifically, suchinformation can be retrieved by detecting the time lapsed for moving thelever between its initial and actuated position. In the following thisprinciple will be illustrated by means of a skin-mountable drug deliverydevice comprising a drug-filled reservoir, a pump and a transcutaneousaccess device. Before turning to the control system, an illustrativedrug delivery device will be described in detail.

More specifically, FIG. 10 shows in an exploded perspective view amedical device in the form of a modular skin-mountable drug deliverydevice 400 comprising a skin-mountable patch unit 410 and a pump unit450, this configuration allowing a pump unit to be used a number oftimes with a new patch unit. The drug delivery device 400 comprises apatch unit 410 having a housing 411, a base member 430 with a lowermounting surface adapted for application to the skin of a subject, aninsertable transcutaneous access device in the form of a hollow infusionneedle, and a separate reservoir and pump unit 450. In the shownembodiment the base member comprises a relatively rigid upper portion431 attached to a more flexible adhesive patch member 432 provided witha gripable strip and having a lower adhesive surface providing themounting surface per se. In the shown embodiment the housing containingthe transcutaneous access device is attached to the base plate as aseparate unit, the two elements in combination forming the patch unit.Within the housing a hollow infusion needle 412 is pivotally arranged.

The patch unit comprises first and second openings 415, 416 which may beopen or covered by needle penetratable membranes allowing thetranscutaneous access device to be provided in a sterile unit inside asealed patch unit. The transcutaneous access device is in the form of ahollow needle comprising a first needle portion 413 having a firstpointed end adapted to penetrate the skin of the subject, the firstneedle portion extending generally perpendicular to the mountingsurface, and a second needle portion 414 in fluid communication with thefirst needle portion via an intermediate needle portion 415 and having asecond pointed end, the second needle portion being arrangedsubstantially in parallel with the mounting surface. The needle isconnected to the housing by a mounting means allowing the needle topivot corresponding to an axis defined by the second needle portion,whereby the needle is moveable between an initial sterile position inwhich the first needle portion is retracted relative to the mountingsurface, and a second position in which the pointed end of the firstneedle portion projects through the second opening. Alternatively, asoft cannula with an insertion needle may be used in place of the hollowneedle, see for example U.S. application 60/635,088 which is herebyincorporated by reference.

The housing further comprises actuation means (not shown) for moving theneedle between a retracted and an extended state, and retraction means(not shown) for moving the needle between the extended and a retractedposition. The actuation and retraction means are actuated by gripablefirst and second strip members 421, 422 connected to the respectivemeans through slot-formed openings in the housing, of which the slot 423for the first strip can be seen. The second strip is further connectedto the patch member 432. Arranged on the housing is user-actuatable malecoupling means 440 in the form of a pair of resiliently arranged hookmembers adapted to cooperate with corresponding female coupling means455 on the pump unit. The housing further comprises an actuator 425 forestablishing fluid communication between the pump assembly and thereservoir (see below), and mechanical communication means 426 foractivating and de-activating the expelling means.

The pump unit 450 comprises a housing 451 in which a reservoir andexpelling means are arranged, the expelling means comprising a pump andactuator assembly 470 of the type described with reference to FIGS. 1-4.The reservoir 460 is in the form of prefilled, flexible and collapsiblepouch comprising a needle-penetratable septum 461 adapted to be arrangedin fluid communication with the pump assembly via pump inlet 472 whenthe pump unit is connected to a patch unit for the first time. Thehousing comprises a window 452 allowing the user to inspect the contentof the reservoir.

The control and pump/actuation means, which may be arranged on a PCB orflex-print, comprises in addition to the pump and actuator assembly 470,a microprocessor 483 for controlling, among other, the pump actuation, acontact switch 484 cooperating with the communication means 426 on thepatch unit, signal generating means 485 for generating an audible and/ortactile signal, and an energy source 486.

FIG. 11 shows a further pump unit with an upper portion of the housingremoved. The pump unit comprises a reservoir 760 and an expellingassembly comprising a pump assembly 300 as well as controller means 580and a coil actuator 581 for control and actuation thereof. The pumpassembly comprises an outlet 322 for connection to a transcutaneousaccess device and an opening 323 allowing a fluid connector arranged inthe pump assembly to be actuated and thereby connect the pump assemblywith the reservoir. The reservoir 560 is in the form of prefilled,flexible and collapsible pouch comprising a needle-penetratable septumadapted to be arranged in fluid communication with the pump assembly,see below. The shown pump assembly is a mechanically actuated membranepump, however, the reservoir and expelling means may be of any suitableconfiguration.

The controller comprises a PCB or flex-print to which are connected amicroprocessor 583 for controlling, among other, the pump actuation,contacts 588, 589 cooperating with corresponding contact actuators onthe patch unit or the remote unit (see below), position detectors in theactuator, signal generating means 585 for generating an audible and/ortactile signal, a display (if provided), a memory, a transmitter and areceiver allowing the pump unit to communicate with an wireless remotecontrol unit. An energy source 586 provides energy. The contacts may beprotected by membranes which may be formed by flexible portions of thehousing.

With reference to FIGS. 10 and 11 a modular local unit comprising a pumpunit and a patch unit has been described, however, the local unit mayalso be provided as a unitary unit.

With reference to FIG. 12 a schematic overview of a pump assemblyconnected to a reservoir is shown, the pump assembly comprising thefollowing general features: a fluid inlet 391 in fluid communicationwith a reservoir 390, a safety valve 392, a suction pump per se havinginlet and outlet valves 393, 394 and a pump chamber 395 with anassociated piston 396, and an outlet 397. The arrows indicate the flowdirection between the individual components. When the piston is moveddownwards (in the drawing) a relative negative pressure will build upinside the pump chamber which will cause the inlet valve to open andsubsequently fluid will be drawn form the reservoir through the openprimary side of the safety valve by suction action. When the piston ismoved upwards (in the drawing) a relative overpressure will build up inthe pump chamber which will cause the inlet valve to close and theoutlet valve and the safety valve to open whereby fluid will flow fromthe pump chamber through the outlet valve and the secondary side of thesafety valve to the outlet. As appears, in normal operation the safetyvalve allows fluid passage during both intake and expelling of fluid andis thus “passive” during normal operation. However, in case thereservoir is pressurized (as may happen for a flexible reservoir) theelevated pressure in the reservoir will be transmitted to both theprimary side of the safety valve and, via the pump chamber, thesecondary side of the safety valve in which case the pressure on theprimary side of the safety valve will prevent the secondary side toopen.

In FIG. 13 an exploded view of a pump assembly 300 utilizing the pumpprinciple depicted in FIG. 12 is shown, the pump assembly (in thefollowing also referred to as a pump) being suitable for use with theactuators of FIGS. 1-9 and the pump units of FIGS. 10 and 11. The pumpis a membrane pump comprising a piston-actuated pump membrane withflow-controlled inlet- and outlet-valves. The pump has a general layeredconstruction comprising first, second and third members 301, 302, 303between which are interposed first and second membrane layers 311, 312,whereby a pump chamber 341 is formed by the first and second members incombination with the first membrane layer, a safety valve 345 is formedby the first and third members in combination with the first membranelayer, and inlet and outlet valves 342, 343 are formed by the second andthird members in combination with the second membrane layer (see FIG.14). The layers are held in a stacked arrangement by an outer clamp 310.The pump further comprises an inlet 321 and an outlet 322 as well as aconnection opening 323 which are all three covered by respectivemembranes 331, 332, 333 sealing the interior of the pump in an initialsterile state. The membranes are penetratable or breakable (e.g. madefrom paper) by a needle or other member introduced through a given seal.The outlet further comprises a self-sealing, needle-penetratable septa334 (e.g. of a rubber-like material) allowing the pump to be connectedto an outlet needle. As shown in FIG. 14 a fluid path (indicated by thedark line) is formed between the inlet 321 (see below) and the inletvalve 342 via the primary side of the safety valve 345, between theinlet valve, pump chamber 345 and the outlet valve 343, and between theoutlet valve and the outlet 322 via the secondary side of the safetyvalve, the fluid paths being formed in or between the different layers.The pump also comprises a piston 340 for actuating the pump membrane,the piston being driven by external driving means, e.g. an actuator asshown in FIGS. 1-9.

The pump further comprises a fluid connector in the form of hollowconnection needle 350 slidably positioned in a needle chamber 360arranged behind the connection opening, see FIG. 15. The needle chamberis formed through the layers of the pump and comprises an internalsealing septum 315 through which the needle is slidably arranged, theseptum being formed by the first membrane layer. The needle comprises apointed distal end 351, a proximal end on which is arranged a needlepiston 352 and a proximal side opening 353 in flow communication withthe distal end, the needle and the piston being slidably arrangedrelative to the internal septum and the chamber. As can be appreciatedform FIG. 15 the needle piston in its initial position is bypassed byone or more radially placed keyways 359. These are provided in order toallow steam sterilisation and to vent the air otherwise trapped when thefluid connector is moved forward in the needle chamber.

The above-described pump assembly may be provided in a drug deliverydevice of the types shown in FIGS. 10 and 11. In a situation of usewhere the pump unit is attached to a patch unit the proximal end 532 ofthe infusion needle is introduced through the outlet seal and septum 334of the pump, and the actuator 425 (see FIG. 10) is introduced throughthe connection membrane 333. By this action the connection needle ispushed from its initial position as shown in FIG. 15 to a actuatedposition as shown in FIG. 16 in which the distal end is moved throughthe inlet membrane 331 and further through the needle-penetratableseptum of a nearby located reservoir, this establishing a flow pathbetween the reservoir and the inlet valve via the proximal opening 353in the needle. In this position a seal is formed between the needlepiston and the needle chamber.

As appears, when the two units are disconnected, the proximal end 532 ofthe infusion needle is withdrawn from the pump outlet whereas theconnection needle permanently provides fluid communication between thepump and the reservoir.

Turning to the above-mentioned operation and performance control bymeans of elapsed time detection for actuator lever movement between aninitial and an actuated position or vice versa, FIG. 17 shows a flowchart illustrating the sequence of operations carried out for animplementation of this principle. More specifically, signals providedfrom sensors or switches adapted to detect that an actuator member(here: the lever) or a component functionally coupled to the actuatorsuch as the above-described piston which is considered a part of theactuator although it may be integrally formed with the pump) has reachedits initial respectively actuated position during an actuation cycle isfed to a processor (e.g. microprocessor). The sensors/switches may be ofany suitable type, e.g. electrical, optical or magnetic. If the initialand/or the actuated position cannot be detected, the processor detectsan error condition which may be related to the type of non-detection.For example, when the actuator is used for the first time, non-detectionof one or both signals may be indicative of an inherent fault in theactuator/pump/device and a corresponding alarm condition may beinitiated. In most cases it will be relevant to define a time windowwithin which the two positions have to be detected during an actuationcycle, this in respect of both the actuation movement between theinitial and actuated position and the return movement between theactuated and initial position. Correspondingly, if the time lapsedbetween the detection of an initial-to-actuated or actuated-to-initialmovement falls outside the time window an alarm condition indicating amalfunctioning may be initiated as will be described in the followingwith reference to a number of examples. When calculating the time lapsedthis may be based on two “real time” time stamps or a timer may be usedwhen movement between the two positions is initiated.

Turning to “normal” operation conditions, the lapsed time for movementbetween the initial and the actuated position (or between the actuatedand the initial position) is calculated and compared with set time valueranges (e.g. pre-set or calculated ranges). Depending on the relationbetween the time lapsed and the set time value ranges a givenpre-defined signal (or non-signal) is output from the processor whichmay then be utilized to perform a given action relevant for the deviceor system in which the actuator and control system is implemented.

Whereas a general example of an actuator operation and performancecontrol principle has been described above, a more specificimplementation of the principle will be described with reference to adrug delivery device of the type described above.

During operation of the pump after priming of an initially empty pump,liquid drug is sucked from the flexible reservoir into the pump chamberas the piston/actuator returns from an actuated to an initial position,whereas liquid drug is pumped from the pump chamber out through thetranscutaneous access device as the piston/actuator is moved from theinitial to the actuated position. During normal operation of the pumpthe time used for both of these pump strokes can be assumed to benear-constant as the conditions remain substantially unchanged. However,during operation of the pump certain conditions may arise which willinfluence operation of the pump and thereby potentially also of theamount of drug delivered. A major concern associated with infusion ofdrugs is occlusion of the access device.

A problem with existing drug delivery pumps is their ability to detectocclusions, especially when the pump is used for low flow applications.The problem is caused by the combination of low flow and compliance ofthe pump as it can take several hours for a blocked pump to build upenough pressure before the occlusion detector gives an alarm. Manytraditional delivery pumps are compliant because the reservoir is partof the pump mechanism and/or because the fluid passage from the pump tothe point of delivery (e.g. the distal end of an infusion needle) iscompliant.

Using a membrane pump as a suction pump in a drug delivery device, ahydraulically much stiffer system can be achieved as the reservoir is“behind” the pump. Correspondingly, by also paying attention to thecompliance of the outlet portion of the system a very stiff system maybe provided such that an eventual occlusion will give an instantpressure increase, making it possible to alarm the user of an occlusionsignificantly faster than with traditional pumps. However, instead ofproviding an additional pressure sensor, the present invention canutilize that occlusion downstream of the pump will result in longer pumpcycles for the outlet stroke given the same force is applied from thepump membrane actuator.

A further condition that would be desirable to detect would beunder-dosing due to backflow of drug to the reservoir during theexpelling stroke in case of malfunctioning of the inlet valve, e.g. whendrug particles are captured in the valve. For such a condition it can beexpected that the outlet stroke cycle will be shorter as a portion ofthe drug in the pump chamber is pumped backwards through the open inletvalve. In addition, this situation may also result in a shortenedsuction stroke as flow resistance through the open inlet valve may bereduced. On the other hand, in case of (partial) inlet valve occlusion,the suction stroke will result in longer cycle times. A longer suctionstroke time may also be indicative of the reservoir being (close to)empty.

As the pump unit of FIGS. 10-16 is supplied with both a sealed reservoirand a sealed pump, it is necessary to prime the pump with liquid drugwhen a new pump unit is connected to a patch unit for the first time.Correspondingly, when the pump controller detects this condition, apriming cycle is initiated. For example, the pump may be operated for agiven number of cycles corresponding to the volume of the pump whereafter it is assumed that no gas remains in the pump. As gas has a muchlower viscosity than a liquid drug, it can be assumed that a pumppartially filled with air will have shortened cycle times for inletand/or the outlet strokes. Correspondingly, by monitoring the cycletimes during priming it can be controlled that the pump has beenproperly primed. For example, a priming cycle is started whereby thepump is actuated in accordance with a predetermined priming cyclefrequency, and a first series of time lapsed values (in the followingalso time value or T) for movement of the pump membrane actuatorassociated with the pumping of a gas or a mixture of gas and liquid isdetected. The detected time values are compared with a value associatedwith the pumping of a liquid. The latter may either be predefined or becalculated dynamically on the basis of the values detected by a seriesof pump strokes known to represent the pumping of air. In case the timevalues for a dry and a wet pump are similar, the controller may useanother condition to determine that the pump has been properly primed,e.g. a rise in time values due to pumping of liquid though a restrictionin the flow conduit downstream of the pump, or due to the liquidentering the subcutaneous tissue of the user. In case the detectedvalues (i.e. one or more) are within the pre-specified or calculatedrange, the priming cycle is ended. In case the detected values are notwithin the range, the priming cycle continues. In case the primedcondition is not identified within a given pre-defined period, amalfunction condition can be identified. For the time values the suctionstroke, the expelling stroke or both may be used as a basis fordetermining whether priming has taken place successfully. Alternatively,instead of comparing the detected time values with a preset orcalculated specific value, it would also be possible to operate the pumpuntil a steady state was achieved, i.e. the time pattern for apre-defined number of operations vary within only a predefined range.

The processor should be adapted for compensating for “normal” bounce ofthe sensors/switches, however, excessive bouncing may be registered as amalfunctioning condition. Further, registering passive movement of theactuator during non-actuated periods may also be utilized to register amalfunctioning condition.

With reference to FIGS. 18-22 a number of examples based on experimentsconducted with a prototype version of the pump assembly shown in FIGS.13-16 will be described. Each data pump represents an actuation of thecoil actuator.

Example 1 Sticking Valves

In order to get very tight valves the surfaces of the valve seats aswell as the rubber membranes are polished. This leads to stickingbetween the valve seat and the membrane. This phenomenon was reflectedon the pump stroke duration measurements as shown in FIG. 18. At datapoints #1-15 a freshly assembled, dry pump is pumping air. The valvesare sticking which is why the stroke durations are relatively high. Atdata point #16 the inlet valve gets wet which eliminates the stickingand a fall in inlet stroke duration is seen. A few strokes later theliquid reaches the outlet valve with a similar effect on outlet strokeduration.

Example 2 Priming Detection

FIG. 19 shows the duration of a series of output strokes and a series ofinput strokes. Data #1-5 shows filling of the conduit connecting thepump to a transcutaneous access device in the form of a hollowhypodermic needle. Output strokes are faster than input strokes becausethe output stroke is driven by an actuator delivering a high forcecompared to the input stroke which is driven by the elastic force of thepump membrane itself. At data point #5, the liquid reaches the needle(ID 0.15 mm, 40 mm long) which represents a significantly higher fluidresistance than the connecting channel (ID 0.50 mm) between the pump andthe needle. At this point a significant rise in output stroke duration(T-out) is observed. No change is observed at the input stroke duration(T-in). At data point #7 the needle is completely filled, which is whythe output stroke duration stabilizes at a new level. This shift inoutput stroke duration can be used to determine when the pump is primed.In case a larger-bore cannula is used as an alternative to a hypodermicneedle, a hollow needle may still be used, e.g. to connect a pump unitwith a patch unit.

Example 3 Occlusion Detection

FIG. 20 shows what happens if the inlet or the outlet from the pump isoccluded. Data points #7-11 show the duration of outlet stroke and inletstroke when the needle of example 2 is filled with liquid and neitherinlet nor outlet is blocked. At data point #11 the outlet is blocked. Atthe following pump stroke the actuator does not reach its bottom stopposition, or does it with a considerable delay. This signal can be usedfor a very fast and early detection of outlet occlusion. At data point#14 the blocking of the outlet is removed. At data point #16 the inletis blocked. At the following pump stroke the actuator does not reach itstop stop position. This signal can be used for detection of occlusionson the pump inlet. The latter can also be used to detect that a flexiblereservoir is close to empty, however, in such a case the rise in T-inwill be less dramatic with only a slow rise, but may still be sufficientto detect a close-to-empty reservoir condition.

Example 4 Bubble Detection

FIG. 21 shows what happens if a bubble is passing through the pump. Datapoints #18-23 show the normal situation where the patient needle isfilled with liquid and no bubbles are present in the pump. At data point#23 an air bubble enters the pump inlet. At this point the inlet strokeduration lowers significantly due to the lower viscosity of air comparedto liquid, e.g. insulin. At data point #24 the same effect is seen atthe outlet stroke duration. At data point #28 all rests of the bubble iscleared from the inlet channel and at data point #33 all bubble restsare cleared from the outlet channel. In both cases the shift from partlyair (bubble) to no air gives leads to a significant rise in strokeduration because of the different viscosity. One of these signals or acombination of them can be used for detecting if a bubble is entering orpassing through the pump. Although a single bubble may not represent amalfunctioning of the pump or the pump-reservoir system, the aboveexample shows that the principles of the present invention can be usedto detect even very minor events.

Example 5 Air Detection

FIG. 22 shows what happens when the pump starts to pump air instead ofliquid, e.g. insulin, which may happen when the flexible reservoirdisengages from the pump inlet or when a major air leak develops betweenthe pump and the reservoir. Data points #33-38 show normal pumping witha pump and needle filled with liquid. At data point #38 air enter theinlet and one or two pump strokes later it reaches the outlet channel.This is in both cases seen as a significant fall in pump stroke durationdue to the significant difference in viscosity between liquid and air.

Example 6 Dynamic Range Calculation

Dependent upon the actual design of a given pump, it may be found thatthere is only minimal variation between the pumps and that substantiallythe same time values are detected when pumping e.g. dry or wet. For sucha pump design it may be desirable to use pre-set time ranges. However,for a different pump design there may be some variation between theindividual pumps for which reason it may be desirable to calculate a setof time ranges for the individual pump based on well-defined pumpconditions. For example, if the pump characteristics are different for adry and a wet pump as shown in FIG. 18, the first e.g. 10 strokes may beused to calculate an average “dry” value which then forms an open rangefor defining when the pump has been filled and reached its “wet” stage.The wet range may be defined by a factor, e.g. a T-in drop of 50% ormore, or a numeric value, e.g. a T-in drop of 100 milliseconds (ms) ormore. The wet value used for comparison may be calculated as an averageof a number of individual values. In case a pump or a pump-patchcombination comprises a downstream constriction in the flow path, e.g. anarrow hollow needle, an average value (defining an open-ended range)based on wet values before the liquid reaches the flow constriction maybe used to determine when the liquid has filled the constriction, seeFIG. 19. Correspondingly, such a value may also be used to determinewhen the fluid enters the subcutaneous tissue of a patient as this mayagain change the detected values.

In the above embodiments the time lapsed between two end positions ismeasured, however, one or more additional contacts may be provided toprovide further information in respect of actuator movement during anactuator stroke and thereby allowing the system to detect a furthernumber of conditions. The additional contacts may be without mechanicalcontact (e.g. optical or magnetic) in order not to impair free movementof the actuator. Thus, for any additional contact one or more additionalsets of defined time ranges may be defined, each time range beingassociated with movement of the actuator member in a given directionbetween two given positions and a given actuation force. For example, anear-initial switch could be used to continuously estimatecharacteristics which are more related to pump/membrane properties thanpump resistance, e.g. altering of the pump membrane properties due toprolonged contact with a given drug. In this it will be possible toadapt the pump actuation to the new pump properties.

In the above examples the relation between pump actuation and pumpmember movement has been discussed, however, during normal operation ofan infusion pump the user will normally not relate to the actual pumpstroke pattern as dispensing of drug may be based on volume, e.g. anamount measured in ml or a rate measured in ml per hour, or it may bebased on units of active drug in a given formulation, e.g. a bolus ofinsulin measured in units, or an infusion rate of insulin measured inunits per hour, which is then used to calculate the corresponding numberand the pattern for actuation of the coil.

In addition to the above principles for detection of pump/actuatorconditions, by measuring the delivered energy to empty the pump chamberit is possible to calculate the relative counter pressure in the pump.This energy can be measured by obtaining the integral of current*voltageby time for the movement or it can be calculated by counting the numberof necessary current pulses or the number of timeslots necessary to movethe piston from top to bottom or simply as the time duration if DCcurrent and DC voltage are applied. Indeed, in order to determinepressure based on e.g. P*V the energy consumed by e.g. friction andinitial pump stretching should be deducted. The calculated counterpressure or a specific limit for delivered energy to empty the pumpchamber can be used as an indication of occlusion and used as a triggerfor an occlusion alarm signal. The calculated counter pressure can alsobe used to compensate for mechanical counter pressure sensitivity in thevolumetric accuracy of the pump system by changing the pump frequencydepending on the counter pressure or the time duration to the next pumpstroke. As for the expelling-stroke energy also the energy for thesuction-stroke can be measured in case the pump is actuatedcorrespondingly. This can also be used to indicate abnormal behaviour inthe pump system including the valves. The calculated counter pressurecan be used to decide and optimise the control of the next pistonmovement during the stroke assuming a slow counter pressure variation bytime, e.g. size of current or slope in current ramp or duty cycle inpulse width modulation of current.

Instead of extra contacts/switches for initial, actuated and in-betweenpositions, the system can be designed to monitor the driving power ofthe piston excitation system during the movement of the piston, e.g.timely monitoring of the current and/or the voltage or a specialelectrical measuring signal (e.g. AC signal) can be superposed on thedriving signal and the corresponding signals generated can be picked upby an additional coil.

When the pump described with reference to FIGS. 10-16 is used for thefirst time, the pump is initially empty and air is pumped. As air has avery low viscosity, pumping of air can be used to detect properties ofthe pump system. For example, when the pump is primed the energynecessary for driving the pump membrane between its initial and actuatedpositions can be determined. When the energy necessary for driving thepump membrane between its initial and actuated positions when liquid ispumped subsequently is determined, the difference between the energiescan be used to calculate the energy used for the pump work and thus thepressure in the pump system.

Referring to FIG. 23 a principle example of pump actuation duringpriming and subsequent normal operation is shown. When the pump is firstactuated, the voltage is slowly ramped up until the actuator startsmoving and the first switch is thereby actuated at SW1, this indicatingthat static friction in the pump/actuator system as well as eventualpre-tension in the pump membrane has just been overcome at V-SW1. Whenthe voltage is further ramped up, the elastic pump membrane is stretcheduntil it reaches its end position corresponding to the actuator endposition whereby the second switch is actuated at SW2. The voltage V-SW2necessary for this movement is thus indicative of pump losses duringpumping essentially without load. As liquid is subsequently entering thepump, the voltage is further ramped up during each pump stroke until aprimed state is reached for which a voltage V-SW2′ is used to fullyactivate the pump. Based on the difference between V-SW2 and V-SW2′ theenergy necessary for the actual pump work and thus the pump pressure maybe determined.

Although a linear voltage-time relationship is shown in FIG. 23, anon-linear relationship may prevail under actual pump conditions.Further, when the pump is actuated under normal operation conditions aramp with a different profile may be used, e.g. the ramp may be adjustedto achieve a given pump cycle timing under which the pump operates mostefficiently, e.g. to ensure that the valves operate efficiently withminimum back-flow. Indeed, instead of ramping the voltage also thecurrent may be ramped.

In the above description of the exemplary embodiments, the differentstructures providing the described functionality for the differentcomponents have been described to a degree to which the concepts of thepresent invention will be apparent to the skilled reader. The detailedconstruction and specification for the different structures areconsidered the object of a normal design procedure performed by theskilled person along the lines set out in the present specification. Forexample, the individual components for the disclosed embodiments may bemanufactured using materials suitable for medical use and massproduction, e.g. suitable polymeric materials, and assembled usingcost-effective techniques such as bonding, welding, adhesives andmechanical interconnections.

1. A pump assembly comprising: an actuator lever comprising a support portion and an arm portion having a longitudinal extent, an actuator for moving the actuator lever, a supporting structure, a pump comprising a pump member moveable by actuation of the actuator lever, wherein the pump is adapted to pump a liquid between an inlet and an outlet thereof, the pump inlet is adapted to be arranged in fluid communication with an outlet of a reservoir adapted to contain a fluid drug, the pump outlet is adapted to be arranged in fluid communication with a transcutaneous access device, the pump member performing a pump stroke when actuated by the actuator lever, and wherein the pump further comprises inlet and outlet valves associated with the pump inlet and the pump outlet respectively, and a pump chamber abutting the pump member, the pump member is adapted to perform a pump stroke and a suction stroke when moved between a first and a second position respectively, wherein the pump chamber is caused to contract and expand due to the movement of the pump member, a first stationary pivoting joint formed between the actuator lever and the supporting structure and located at a proximal end of the arm portion of the actuator lever, a second floating pivoting joint formed between the actuator lever and the pump member and located between the first stationary pivoting joint and the support portion of the actuator lever, the second floating pivoting joint allowing the pump member to float relative to the actuator lever, a constant-length actuator arm being defined by a portion of the arm portion of the actuator lever formed between the first stationary pivoting joint and the second floating pivoting joint, wherein the second floating pivoting joint is comprised of a lever joint structure on the arm portion of the actuator lever that cooperates with a substantially planar surface of the pump member, the second floating pivoting joint allowing the actuator lever and the lever joint structure to float relative to the planar surface of the pump member.
 2. A pump assembly comprising: an actuator lever comprising a support portion and an arm portion having a longitudinal extent, an actuator for moving the actuator lever, a supporting structure, a pump comprising a pump member moveable by actuation of the actuator lever, wherein the pump is adapted to pump a liquid between an inlet and an outlet thereof, the pump inlet is adapted to be arranged in fluid communication with a transcutaneous access device, the pump member performing a pump stroke when actuated by the actuator lever, and wherein the pump further comprises inlet and outlet valves associated with the pump inlet and the pump outlet respectively, and a pump chamber abutting the pump member, the pump member is adapted to perform a pump stroke and a suction stroke when moved between a first and a second position respectively, wherein the pump chamber is caused to contract and expand due to the movement of the pump member, a first floating pivoting joint formed between the actuator lever and the supporting structure allowing the actuator lever to float relative to the supporting structure and located at a proximal end of the arm portion of the actuator lever, a second floating pivoting joint formed between the actuator lever and the pump member and located between the first floating pivoting joint and the support portion of the actuator lever, the second floating pivoting joint allowing the actuator level to float relative to the pump member, a constant-length actuator arm being defined by a portion of the arm portion of the actuator lever formed between the first floating pivoting joint and the second floating pivoting joint, wherein at least one of the first and the second floating pivoting joints is comprised of a lever joint structure on the arm portion of the actuator lever that defines one of a line or a point of contact that cooperates with a substantially planar surface on at least one of the pump member and the supporting structure respectively, wherein at least one of the first and the second floating pivoting joints allows the actuator lever and the lever joint structure to float relative to the planar surface of at least one of the pump member and the supporting structure respectively.
 3. A pump assembly as in claim 1 wherein a biasing member is provided and adapted to hold the actuator lever and the supporting structure at the first pivoting joint, and the actuator lever and the pump member at the second floating pivoting joint in contact, respectively, with each other.
 4. A pump assembly as in claim 1, wherein the actuator is a coil-magnet actuator, the coil and magnet(s) being arranged on the actuator lever and the supporting structure respectively.
 5. A pump assembly as in claim 1, wherein the actuator lever is moved between a first position and a second position, the pump assembly further comprising first and second stop means adapted to engage the actuator lever in the first and the second position respectively.
 6. A pump assembly as in claim 5, further comprising: detection means for detecting when the actuator lever has moved to the first and second positions respectively and supplying time signals indicative thereof, and a controller for determining on the basis of supplied time signals the time lapsed when the actuator lever is moved between the first and second positions in a given direction, the controller comprising information representing at least one defined time range, each time range being associated with movement of the actuator lever in a given direction between the first and second positions and a given actuation force, the controller being adapted to compare the determined time lapsed with the defined time range(s) and perform an action corresponding to the time range associated with the determined time lapsed.
 7. A pump assembly as in claim 1, wherein the transcutaneous access device comprises a distal end adapted to be inserted through the skin of a subject, the transcutaneous access device comprising an inlet in fluid communication with or being adapted to be arranged in fluid communication with the pump outlet.
 8. A pump assembly comprising: an actuator lever comprising a support portion and an arm portion having a longitudinal extent, a supporting structure, a pump comprising a pump member moveable by actuation of the actuator lever, an actuator for moving the actuator lever wherein the actuator is a coil-magnet actuator, a first stationary pivoting joint formed between the actuator lever and the supporting structure and located at a proximal end of the arm portion of the actuator lever, a second floating pivoting joint formed between the actuator lever and the pump member and located between the first stationary pivoting joint and the support portion of the actuator lever, the second floating pivoting joint allowing the pump member to float relative to the actuator lever, a constant-length actuator arm being defined by a portion of the arm portion of the actuator lever formed between the first stationary pivoting joint and the second floating pivoting joint, wherein the second floating pivoting joint is comprised of a lever joint structure on the arm portion of the actuator lever that cooperates with a substantially planar surface of the pump member, the second floating pivoting joint allowing the actuator lever and the lever joint structure to float relative to the planar surface of the pump member.
 9. A pump assembly as in claim 8, wherein the coil and the magnet(s) are arranged on the actuator lever and the supporting structure respectively.
 10. A pump assembly comprising: an actuator lever comprising a support portion and an arm portion having a longitudinal extent, a supporting structure, a pump comprising a pump member moveable by actuation of the actuator lever, an actuator for moving the actuator lever wherein the actuator is a coil-magnet actuator, a first floating pivoting joint formed between the actuator lever and the supporting structure and located at a proximal end of the arm portion of the actuator lever, the first floating pivoting joint allowing the actuator lever to float relative to the supporting structure, a second floating pivoting joint formed between the actuator lever and the pump member and located between the first floating pivoting joint and the support portion of the actuator lever, the second floating pivoting joint allowing the actuator lever to float relative to the pump member, a constant-length actuator arm being defined by a portion of the arm portion of the actuator lever formed between the first floating pivoting joint and the second floating pivoting joint, wherein at least one of the first and second floating pivoting joints is comprised of a lever joint structure on the arm portion of the actuator lever that defines one of a line or a point of contact that cooperates with a substantially planar surface on at least one of the pump member and the supporting structure respectively, wherein at least one of the first and the second floating pivoting joints allows the actuator lever and the lever joint structure to float relative to the planar surface of at least one of the pump member and the supporting structure respectively.
 11. A pump assembly as in claim 10, wherein the coil and magnet(s) are arranged on the actuator lever and the supporting structure respectively. 